The immune system operates on the principle of checks and balances. For T cells, there is evidence that their activities may be controlled in part by subsets of T cells specialized in regulation. The thymic-derived CD4+CD25+ T cells belong to one of these subsets. Unlike conventional T cells that function as effector cells during an immune reaction, the CD4+CD25+ T cells act to suppress the activation of conventional T cells and in doing so, actively maintain immunologic tolerance in the periphery (reviewed in references1-3). Recent studies indicate that the CD4+CD25+ T cells may play important roles in the prevention of certain auto-immune and allo-immune diseases4-11.
Given the importance of these regulatory cells, it is critical to understand the mechanisms controlling their activation and expansion in the periphery. Intriguingly, freshly isolated CD4+CD25+ T cells are anergic, proliferating poorly in response to TCR stimulation in vitro. How these cells expand in vivo in response to physiological stimuli has yet to be determined. Recently it has been shown that CD4+CD25+ T cells carrying a transgenic TCR can undergo clonal expansion in vivo in response to immunization with a specific antigen, and that the dynamics of the regulatory cell population depends largely on local environment12-14. In addition to antigen presentation, co-stimulation by activated dendritic cells (DC) is likely to be a key factor affecting the dynamics of CD4+CD25+ T cells proliferation, as it has been shown that the CD4+CD25+ T cells can be expanded in vivo with bone marrow-derived, antigen-presenting DC, in a manner that is dependent on B7 expression14. Interestingly, deficiency in B7 only reduces, but does not entirely eliminate, the potency of DC, suggesting that additional co-stimulators other than B7 may also play a role14. Such a role of additional co-stimulators is consistent with previous evidence that the development of IL-10-secreting, respiratory regulatory T cells depends on ICOS, not B715.
4-1BB (CD137) is a membrane receptor protein of the TNFR superfamily. Like CD28, 4-1BB is a potent co-stimulator, known to promote CD4+ and CD8+ T cell activation and survival (reviewed in reference16). Unlike CD28, which competes for B7 with another receptor, CTLA-417, 4-1BB binds monogamously to a single ligand, 4-1BBL, thereby allowing more straightforward determination. Furthermore, previous studies have indicated that 4-1BB gene expression is upregulated in CD4+CD25+ T cells18, 19.
There is a continuing need in the art for methods of obtaining CD4+CD25+ T cells and overcoming their anergy. If reasonable amounts of CD4+CD25+ T cells were available, they could be used inter alia for drug screening and therapy of immune-related diseases.